Apparatus, method, and system for testing human olfactory systems

ABSTRACT

An apparatus, module, methods and systems for automated, standardized assessment and analysis of a human olfactory system&#39;s odor detection ability as an indicator or predictor of cognitive impairment or change in cognitive health, and other health conditions such as diabetes. Notably, the present invention is operable for use across all age groups of humans and provides quantitative detection and analysis of a human olfactory system&#39;s detection ability compared to a relevant demographic population.

CROSS REFERENCES TO RELATED APPLICATIONS

The present application claims the benefit of U.S. Provisional PatentApplication No. 62/142,726, filed Apr. 3, 2015, U.S. Provisional PatentApplication No. 62/315,870, filed Mar. 31, 2016, and U.S. patentapplication Ser. No. 15/087,181, filed Mar. 31, 2016, each of which ishereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The present invention is generally directed to an apparatus, method, andsystem for testing human olfactory sensory system functions. Moreparticularly the present invention operates to provide a method for theprecise generation of specified olfactory system testing odorants, foruse in making standardized testing of olfactory systems, datacollection, assessment, and predictive or diagnostic results, and evenmore particularly for human olfactory system odor detection, odoradaptation, odor discrimination and odor identification ability toidentify disease or disorder(s) and as a predictive element of cognitiveimpairment.

2. Description of the Prior Art

A decrease in olfactory function with age has been attributed to avariety of factors, including normal anatomical and physiologicalchanges in aging, trauma, environment, exposure to toxins, medications,and disease. A decrease in olfactory function has also been determinedto be one of the best predictors of five-year survival. Other researchshows that changes associated with diseases such as diabetes affectsolfactory function. Cognitive disease or disorder, namely Alzheimer'sdisease, Parkinson's disease, traumatic brain injury, Amyotrophiclateral sclerosis (ALS) and schizophrenia, are known to be associatedwith olfactory dysfunction. In particular, the ability to identify anddiscriminate the odors, as well as the odor threshold, can be altered incognitive disorders. These changes often occur as early manifestation ofthe cognitive pathology but they are not always diagnosed on time. Earlydiagnosis can lead to slowing, stopping, or reversing the progression ofcognitive decline.

U.S. Pat. No. 6,059,724 for system for predicting future health byinventors Campell, et al. filed Feb. 14, 1997 and issued May 9, 2000 isdirected to a computer-based system for predicting future health ofindividuals comprising a computer comprising a processor containing adatabase of longitudinally-acquired biomarker values from individualmembers of a test population; a computer program that includes steps forselecting from said biomarkers a subset of biomarkers for discriminatingbetween members, and using the distributions of the selected biomarkersto develop a statistical procedure that is capable of being used forclassifying members of the test population, and estimatingquantitatively, for each member of the test population, the probabilityof acquiring the specified biological condition.

U.S. Pat. No. 6,325,475 for devices for presenting airborne materials tothe nose by inventors Hayes, et al. filed Apr. 21, 1997 and issued Dec.4, 2001 is directed to an ink-jet dispenser for the micro-dispensationof airborne materials into an individual's airspace for inhalation orsniffing. The ink-jet dispenser will allow the study of temporalintegration times, inter-nostril summation, backwards and forwardsmasking, and other olfactory phenomena.

U.S. Pat. No. 6,338,715 for digital olfactometer and method for testingolfactory thresholds by inventors Hayes, et al. filed Mar. 31, 2000 andissued Jan. 15, 2002 is directed to a more reliable and precise methodof determining the olfactory threshold is provided by a digitallyoperated apparatus that dispenses controlled amounts of a volatile testfluid from a digital jetting device of the type used for ink jetprinting. A precise number and size of micro droplets are dispensed ontoa heater which vaporizes the fluid at a test location where a patientcan sniff and report whether the odor is sensed. Incremental adjustmentsare made to determine the approximate threshold of olfactory perceptionof the odor. Sensors are included to verify dispensing and to coordinatedispensing with breathing.

U.S. Pat. No. 6,557,394 for smell test device by inventor Doty filedApr. 2, 2001 and issued May 6, 2003 is directed to a test for assessinga person's sense of smell and more particularly, toward a test which iseasy to use and can be evaluated by the individual taking the test.

U.S. Pat. No. 8,429,950 for field olfactometer with differentialflow-based dynamic dilution by inventor Wright filed Aug. 5, 2010 andissued Apr. 30, 2013 is directed to a low-cost field olfactometer thatmay be used to determine when an environmental odor is present in theambient air in an amount which is at or above a predetermined dilutionratio. The invention also encompasses a method of olfactometry and areplaceable diluent filter cartridge assembly employed in theolfactometer and olfactometry method.

U.S. Pat. No. 8,469,293 for digital odor generator by inventors Doty, etal. filed Apr. 16, 2010 and issued Jun. 25, 2013 is directed to adigital odor generator or olfactometer and, more particularly, toward adigital odor generator that can be used to administer various odorsalone or in various combinations to a patient or subject. The digitalodor generator of the invention can also be used to administer olfactorytests remotely over the Internet or other network and to collect theresults and tabulate data over such networks.

U.S. Pat. No. 8,820,265 for high-throughput operant sensorydiscrimination apparatus and method by inventors Palmer and Salemmefiled Dec. 6, 2005 and issued Sep. 2, 2014 is directed to apparatus andsystems useful in sensory discrimination. Through the use of amulti-well sample plate, the high-throughput analysis apparatus andmethod allow for rapid sensory discrimination of a large number ofsamples.

US patent application 2007/077,204 for olfactory identification testsfor cognitive diseases and disorders by inventors Devanand, et al. filedApr. 13, 2006 and issued Apr. 5, 2007 is directed to smell tests (odoridentification tests) that are shorter that UPSIT, yet has a statisticalsensitivity and specificity equivalent to or better than UPSIT. The odoridentification tests of the invention are based on a core set of sixodorants, where the six odorants can be selected from the followinggroup of odorants: menthol, clove, leather, strawberry, lilac,pineapple, smoke, soap, natural gas and lemon. The invention providesodor identification tests that can: (1) discriminate between subjectswho are normal and who have a neuropsychiatric condition, cognitivedisease or disorder, and/or (2) predict which subjects with mildcognitive disorders will develop various neuropsychiatric conditions orcognitive diseases and disorders. In one embodiment, the test andmethods of the invention can provide an early prediction or diagnosis ofAlzheimer's disease that is important for patients (including patientswho have mild cognitive disorders, such as MCI) and clinicians to makeplans for the future and to institute early treatment.

SUMMARY OF THE INVENTION

The present invention is generally directed to an apparatus, methods,and systems for providing standardized testing of human olfactorysystems. More particularly, the present invention operates to providetesting, data collection, assessment, and predictive or diagnosticresults for human olfactory systems and even more particularly for humanolfactory system odor detection, discrimination, odor adaptation, andidentification abilities to aid in identifying mental disease, healthdisorders, health conditions and serve as a predictive element ofcognitive impairment.

The invention is further directed to a standardized olfactory populationdatabase for automated quantitative comparison and analysis of theolfactory system of a human based on standardized measures. Theinvention is still further directed to an automated odorant-deliverycartridge for use with automated apparatus, method and systems of thepresent invention. The invention is still further directed to a modulefor connecting a cartridge to a mobile computing device. The inventionis further directed to a method for presenting standardized odorants andstandardizing the collection of olfactory test data. Specifically, inone embodiment, the invention standardizes odorant concentrationcalibration and a delivery system, so that regardless of the location ofone or more of the devices of the present invention, the devices willdeliver the same, known odorant concentration(s). Advantageously, thisapproach allows for repeated testing of a patient, longitudinal testing,and development of a normative database and an Olfaxis Index forobjectively quantifying degradations in olfactory function. Anotheradvantage of this approach is in providing testing of a new patient andcomparing their test results with a normative appropriate demographicpopulation where all olfactory measures were collected with identical,standardized odorants. Advantageously, this is possible with one test ofthe new patient. In contrast, the prior art requires repeated, long termtesting of the new patient to compare the new patient's results with thenormative appropriate demographic population.

The present invention provides systems and methods for the quantitativeexamination and analysis of a person's odor detection (odorsensitivity), discrimination, odor adaptation, and odor identificationabilities, wherein the system includes a device and database thatcommunicate; wherein the device is automated and the database housesvarious population distributions of odor response abilities as astandard of comparison. More specifically, this system includes at leastone device in wired or wireless electronic network communication with aserver, wherein the server is in communication with the database ofpopulation distributions. If the server is not currently connected tothe device, the device is operable to store the demographics of thepatient/subject, the results of the patient/subject, and upload theresults of the patient/subject upon a connection becoming available.

The system provides for devices to independently and autonomouslytransmit and receive data to and from the server. The server, which maybe a remote server computer in network-based communication with thetesting apparatus or device, compares received results to the individualpatient's previous measures and/or to the population database for one ormore odorants to quantify an Olfaxis Index of olfactory function. Thisreal-time or near-real-time analysis and reporting of data enables therapid screening and comparison of test subjects. Thus, the presentinvention provides for comparing a person's olfactory performance to astandard (their own longitudinal or their own baseline, and/or againstan appropriate demographic). The Olfaxis Index can aid in diagnosticsfor a multiplicity of conditions. Significant olfactory dysfunction canput a person at risk of smoke/fire, eating spoiled food, change of dietto a more unhealthy diet (more sugar, salt and fat), be related todiabetes, be symptomatic of traumatic brain injury, myasthenia graves,ALS, and as a biomarker for AD and PD. The prior art fails to provide,teach or suggest such a system and corresponding methods.

These and other aspects of the present invention will become apparent tothose skilled in the art after a reading of the following description ofthe preferred embodiment when considered with the drawings, as theysupport the claimed invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a cartridge according to the present invention.

FIG. 2 illustrates another cartridge according to the present invention.

FIG. 3 illustrates a module according to the present invention.

FIG. 4 illustrates an olfactory measurement apparatus according to thepresent invention.

FIG. 5 illustrates another olfactory measurement apparatus according tothe present invention.

FIG. 6 illustrates a system according to the present invention.

FIG. 7A, 7B, and 7C illustrate population distributions of normalcognitive decline associated with ageing.

FIG. 8 illustrates an individual's longitudinal results compared to apopulation distribution over time.

FIG. 9 illustrates another testing system according to the presentinvention.

FIG. 10 is a schematic diagram of an embodiment of the inventionillustrating a computer system for use with the present invention.

FIG. 11 illustrates a basic method for assessing cognitive decline.

FIG. 12 is a carrier gas assembly showing two parallel carrier chamberswith their outputs coupled.

FIG. 13 is an odorant assembly with a semi-transparent body showing thepiston in a closed position according to the present invention.

FIG. 14 is an odorant assembly with a transparent valve body showing thepiston in a partially retracted position according to the presentinvention.

FIG. 15 is an odorant assembly side view showing odorant reservoir withan ultrasonic transducer below the valve body.

FIG. 16 is a schematic diagram of a system according to the presentinvention.

DETAILED DESCRIPTION

The present invention provides an apparatus, method, and system forstandardized testing of human olfactory system functions. The inventionincludes an automated, standardized odor-delivery cartridge and odorantconcentration measurement and calibration system for use with a testingapparatus having a controller for running the test sequence andcapturing user input, with calibrated air flow or adapted to beconnected with a smartphone or tablet computer or other computing devicethrough a module. Preferably, the apparatus includes a photoionizationdetector (PID) to measure and/or calibrate the odor delivery cartridge.The apparatus is in electronic communication with at least one servercomputer and at least one database, preferably within a cloud-basedcomputing network for providing real-time or near-real-time analysis ofthe data.

The prior art is limited regarding a standardized automated device,standardized odorants, method, or system for assessing overall olfactoryfunctional status and predicting cognitive impairment based on odordetection, odor discrimination, odor adaptation, and odoridentification. The prior art does not disclose a standardized odorant.

Thus, there is a long-standing, unmet need for a standardized, automateddevice, method, and system that can accurately and quantitativelyexamine and analyze a person's odor detection ability against their ownhistory and against an appropriate demographic population, quantifychanges in olfactory function over time, or identify dysfunction bycomparing smell function against a standardized, demographic database(quantify an Olfaxis Index) in order to aid in the identification ordiagnosis of physical health conditions, and to better predict aperson's risk for cognitive impairment and/or other mental and relatedcomplications. The present invention solves this long-felt but unmetneed by providing sealed cartridges/ampules and photoionizationdetectors to provide standardized concentrations of odorants.

The prior art, including U.S. Pat. No. 6,059,724 and others, fails tostandardize olfactory measures. The present invention differs bystandardizing olfactory measures, which allows for comparison of a newindividual to the population metric (an Olfaxis Index). Standardizationis essential for creation of an Olfaxis Index, and estimatingquantitatively for each member of a test population, the probability ofacquiring a specified biological condition (mental or physical). Thepresent invention fulfills this long-standing unmet need by providingstandardization of olfactory measures.

U.S. Pat. No. 6,338,715 describes that a precise number and size ofmicro droplets are dispensed onto a heater which vaporizes the fluid ata test location where a patient can sniff and report whether the odor issensed. However, this approach is disadvantageous as the precise numberand size of micro droplets assumes a chemical condition and there is noactual measure of concentration. By contrast, the present invention isadvantageous in that it provides standardized concentrations. Also, theprior art reference is disadvantageous because dispensing the microdroplets onto a heater changes the molecular structure of the microdroplets, which could yield a different odor than the original unheatedmicro droplets.

U.S. Pat. No. 6,557,394 does not disclose measuring sensitivity of aperson to an odor. Additionally, this patent document requires the testsubject to (1) smell the odor and (2) identify the odor. Thus, if aperson incorrectly identifies an odor or fails to identify the odor, itcould be because the person can't smell the odor or the person can'tidentify or remember the name of the odor. Thus, this patent documentrequires a cognitive component, unlike the present invention which iseffective at measuring smell using standardized odors. The presentinvention provides for measuring sensitivity of a person to an odor,which is a long-felt unmet need in the prior art.

U.S. Pat. No. 8,469,293 does not disclose standardized odorants. Thegenerator is also costly, difficult to set up, use, and clean. Incontrast, the present invention is cost effective, easy to set up, use,and clean.

US patent application 2007/077,204 does not describe measuring asensitivity or threshold as in the present invention. Additionally, thispatent document does not describe adapting to deterioration of testodorants, different temperatures, and/or humidity. There is nostandardized measure disclosed by this patent document. There is also arequirement of a cognitive component to identify the odor in this priorart patent document.

Additionally, unlike the prior art, the present invention provides formeasuring and standardizing olfactory functions of people of all agesfor a variety of physical and mental conditions. While the presentinvention is operable for detecting the likelihood of a patientdeveloping or detecting that a patient has developed Parkinson's andAlzheimer's, the present invention also provides for the detection of avariety of other disease across all age ranges. Specifically, thepresent invention is operable for detection of diabetes, exposures totoxins, allergies, and/or idiopathic conditions and diseases as well aspredicting the onset of such conditions.

Cartridge

The present invention provides for a cartridge, generally described as10 in FIGS. 1 and 2, for providing odorant for testing human olfactorysystems. A cartridge is a small modular unit designed to be insertedinto a larger piece of equipment. The cartridge houses, contains, orholds an odorant 12 for testing, and is connectable, by wire orwirelessly, to a computing device, which maintains control and commandof the cartridge and receives input of testing results. In anotherembodiment, the cartridge houses, contains, or holds more than oneodorant for testing, depending upon the nature of the test being run(threshold sensitivity, adaptation, odor identification, etc.). In theevent that no network connection is available between the mobilecomputing device and the cartridge, the cartridge is operable tofunction independent of the mobile computing device and upload data tothe mobile computing device upon restoration of a network connectionbetween the cartridge and the mobile computing device. Thus, thecommunication between the cartridge and the computing device confers thedelivery of the odor from the cartridge. The cartridge is smaller thanodorant holders in olfactometers of the prior art and thus it isportable and disposable. The cartridge contains or holds the odorant,wherein, by way of example and not limitation, the odorant is a liquid,semi-solid, solid, or absorbed or adsorbed onto a support. The cartridgeverifies that the contents match the correct stimulus paradigm bycomparing the bar code on the cartridge to match the odorant andolfactometer system airflow and other operational parameters. Thecartridge is also operable to verify purity for calculations of mixingto a specified percent concentration.

The cartridge 10 is preferably a sealed container constructed andconfigured to allow air to flow over at least one odorant 12 forcreating an odor provided or presented to a human being tested. Thecartridge 10 is a liquid- and odor-impermeable body and is filled withan inert gas designed to confine and preserve the odorant and the odoruntil the cartridge is activated. Activation of the cartridge includesany method for creating an opening into the cartridge for release of theodorant within. In a preferred embodiment, the cartridge includes animpermeable body 14 and an opening 18 that is sealingly engaged with animpermeable, pierceable cover 20 to form the liquid-impermeable,chemical-impermeable, and/or odorant-impermeable cartridge 10. Thecartridge is permanently sealed with an impermeable cover, or ahermetically sealed glass ampoule to prevent odorant chemicaldeterioration, evaporation or oxidation to preserve odorant quality. Thecartridge is preferably activated by puncturing the impermeable cover bypiercing with an air inlet tube 22 and an air outlet tube 24 when thecartridge is inserted into an apparatus and activated. In an alternativeembodiment, the impermeable body 14 is also pierceable. In anotherembodiment, the cartridge includes a glass ampoule that is broken insidea reservoir on use to ensure purity.

Preferably, the impermeable cartridge 10 holds a given volume of liquidodorant 12, the air inlet tube 22 sparges air through the odorant fluid12, and the resulting air with odorant vapor exits the cartridge throughthe air outlet tube 24. In an alternative embodiment (FIG. 2), anodorant support 26 is disposed within the cartridge body to hold a solidor semi-solid odorant. The inserted air inlet and air outlet tubes arepositioned relative to the odorant support in order to direct the flowof air over the odorant and prevent bypassing the odorant. Inalternative embodiment, the support is a filter and the odorant issprayed on the filter and allowed to dry. In another alternativeembodiment, the support is a gel and the air inlet tube pierces throughthe gel, and then flows air over the surrounding gel. For creating theodorant with the ampoule, the glass ampoule is broken or dispensed intoa reservoir.

The airflow tubes are separate, as shown in FIG. 1 or co-axial, as shownin FIG. 2. The co-axial tube system only requires the cover to bepierced in one location, thus reducing the risk of leakage around thetubing system.

In an alternative embodiment, the odorant and odorant support arepartitioned in the cartridge body by at least one partition, wherein thepartitioning allows vapor to fill the headspace of the cartridge bodybut restrict solid or semi-solid odorant particulate from entering theheadspace, therein preventing particulate from entering the air-outlettube. Example embodiments include U.S. Pat. Nos. 6,658,989, 6,645,537,6,607,762, 6,589,577, 5,840,189, 5,325,765 and US Patent PublicationNos. 20130270176, 20130156897, each of which are incorporated byreference herein in their entirety.

Cartridges are designed, constructed, and configured to provide adequateheadspace to meet the volumetric and/or concentration requirements ofthe testing to be performed, such that the necessary amount of odorantis delivered with each test. The headspace is configured and designedsuch that individual test actuations do not significantly diminish theheadspace odor concentration. Additionally or alternatively, theapparatus is designed to control the testing actuation of a cartridgesuch that the headspace odor concentration is not significantlydiminished. In other words, the apparatus will not actuate a test ifinsufficient headspace odor concentration is predetermined based onusage. In another embodiment, the test device and/or cartridge canpreferably determine the absolute concentration or recognize the changein vapor pressure or volume or concentration of the odorant andcorrespondingly alter the airflow through the cartridge and/or alter themixing with the carrier air so that the proper amount and concentrationof the odorant is delivered. Thus, the odorant concentration in thecartridge is calibrated for each odorant delivery. In anotherembodiment, a separate, disposable reservoir is utilized for creatingthe odorant, with the cartridge preferably releasing the odorant intothe reservoir.

The present invention thus provides for a cartridge for providingodorant for testing human olfactory systems. A cartridge is a smallmodular unit designed to be inserted into a larger piece of equipment.More particularly, the cartridge used in the present invention isdesigned and configured to contain an odorant and fit into a testerapparatus as described herein. The cartridge is not configured ordesigned for resealing after activation. In another embodiment, thecartridge is designed and configured to prevent resealing. The cartridgeis a puncture-activated, non-refillable, non-resealable modularcontainer with odorant that is standardized to provide a predeterminednumber of tests at a predetermined concentration and fit into a testerapparatus as described herein.

In a preferred embodiment, each cartridge also incorporates anidentifier 32, such as a digital chip, bar code, etc., within, or aboutthe cover or body to identify the odorant(s) in the cartridge. Theidentifier is automatically detected and read by a reader 33 and theinformation used to regulate the air flow and actuation rate of thecartridge. The identifier includes the odorant and/or cartridgecharacteristics necessary to perform the test. For example, theidentifier includes the name of the odorant, carrier, concentration incarrier, headspace of the cartridge, maximum flow rate through thecartridge, maximum total odorant available, the vapor pressure, vaporionization voltage, and any other chemical properties necessary tocreate a specified concentration of the odorant. The information fromthe identifier is communicated to the device and/or remote server tocalibrate testing and standardize, normalize or otherwise correct testdata for the particular odorant cartridge's properties.

In alternative embodiment, a cartridge is automated to present an odorto and obtain information from a person. Following odor presentation,the module or controller receives the user response data. The responsedata preferably are provided to a mobile computing device thatcommunicates the response data with other system components.

More specifically, the cartridge houses a chip or other identifierpre-programmed to identify the odorant(s), total actuatable mass orvolume of the odorant(s), and/or concentration of the odorant(s) in theheadspace of the cartridge, all of which are communicated to the device.Preferably, the chip also is operable to measure a vapor pressure of theodorant. The vapor pressure is preferably used to calculate vaporconcentration. The total acuatable mass or volume is the total volume,mass or amount of odor that can be delivered by test actuation from anygiven cartridge without affecting the concentration of the odorant andthe reliability of testing. This volume or amount or concentrationpreferably remains constant for each cartridge type or test session.Verification of the concentration in the headspace or otherconcentration verification is used to indicate when the cartridgereplacement is required (i.e., when the concentration is too low or thecartridge is spent). Preferably, verification of the concentration isperformed via a photo ionization detector. The testing device controlsand varies the delivered test air volume and test frequency. Thedelivered test air volume will vary based on the desired concentrationto deliver to the subject and from presentation to presentation for thesubject. The test frequency or trial rate (number of tests per timeperiod) will vary based on the previous test air volume delivered,wherein the limiting factor for test frequency is the time required tosaturate the headspace or otherwise ensure that the cartridge headspacehas the proper odor vapor concentration, which is dictated by odorant(s)volatility and airflow.

In a preferred method, the total airflow delivered to the person beingtested is constant. At the initial activation of a cartridge, the odorconcentration is determined and the appropriate amount of airflow iscalculated to provide adequate odor concentration for all programmedtests, e.g., for a given test session or patient or until theconcentration is too low to continue (and then a new cartridge is usedto replace the spent cartridge). Thereupon, for all tests the carrierairflow is adjusted to ensure constant delivered airflow and/or constantconcentration while providing the appropriate odor concentration for thetest. Delivered airflow is adjusted if the concentration or volume ofodorant deteriorates.

The number of tests delivered per cartridge is not constant, but ratheris determined by the odorant(s) physical properties and quantity and thedesired delivered test air volumes.

In an alternative embodiment, the odorant is incorporated into a polymer(or other medium or containment vessel that will release odorant) thatvaporizes the odorant when electrically-stimulated.

Module

The present invention includes a module, generally described as 40 inFIG. 3, designed, constructed and configured for accepting at least onecartridge containing an odorant or selection or group of odorants to beused for testing human olfactory systems.

Preferably, the olfactometry module includes an adaptor designed,constructed and configured for accepting and activating apuncture-activated, non-resealable cartridge with an odorant, anidentifier and a headspace, the cartridge standardized to provide apredetermined number of tests at a predetermined concentration into theolfactometer, a detector for measuring the gas-borne concentration ofthe odorant in the headspace of the cartridge, a reader for reading theidentifier to determine information used to regulate gas flow within thecartridge, an air flow generator, and a network port for communicatingwith a computing device to provide testing data to a system for analysesand storage. The module preferably includes a database of test results.

The module is a portable and preferably wireless component thatcommunicates with a mobile computing device to provide testing data to asystem for analyses and storage, wherein the mobile computing device is,by way of example and not limitation, a smartphone, watch, tablet, orlaptop computer. The module is preferably operable to connect to thecloud, the Internet, or another device via a network for analyses andstorage. The module also preferably includes a system for analyzing andstoring data if a network connection is unavailable. Preferably, themodule uploads the analyzed and stored data to a database over a networkupon restoration of the network connection. In another embodiment, themodule includes a local copy of the database. Preferably, the local copyof the database was downloaded during the last network connectionbetween the module and the mobile device. The module preferably includesan adaptor, wherein the adaptor accepts the at least one cartridge,thereby initiating function of the module. In a preferred embodiment,the module has receivers 46 for multiple cartridges 10, provides dials51 that regulate the air flow through the cartridges, and provides a fan49 for generating air flow. Although dials are provided in oneembodiment, the airflow is preferably determined by PID measures of aconcentration or volume of the odorant. In alternative embodiments, thedials are electronic and/or the air flow generator is manual.

The module includes an electronic network port 47 for electroniccommunication, such as, by way of example and not limitation, USB ordongle, or wireless, such as, by way of example and not limitation,Bluetooth or NFC.

In yet another embodiment, the module is for personal use and inelectronic communication with a mobile computing device, which is incommunication with a server and database. By way of example and notlimitation, the personal module is a dongle. Apparatus for assessingolfactory system odor detection ability to predict cognitive impairmentand health conditions such as diabetes.

Apparatus

The present invention provides an apparatus which improves upon a devicedescribed in Bodyak N and Slotnick B, 1999. Performance of Mice in anAutomated Olfactometer: Odor Detection, Discrimination and Odor Memory.24 (6): 637-645; which is incorporated herein by reference in itsentirety. The present invention provides for a tester apparatus,generally shown as 60 in FIGS. 4 and 5, either stationary or portable,which is pre-configured to accept odorant cartridges 10 or modules 40.These odorant cartridges contain an incorporated odorant that isreleasable in predetermined amounts by the tester apparatus to form anodor in predetermined concentrations. Concentration-determiningvariables include odorant concentration, headspace volume, odorantsurface area, odorant vapor pressure, ambient temperature, humidity, andair flow through the cartridge. Preferably, the tester apparatus isoperable to determine ambient temperature and humidity. The testerapparatus can vary the amount of air flow through the cartridge in orderto vary the amount of odorant released and thereby establish the odordetection abilities of the person being tested. Alternatively, thetester varies the amount of carrier air mixed with the odorized air orthe aerosolized chemical exiting the cartridge to adjust theconcentration of odorant to maintain a constant airflow to the personbeing tested. In another embodiment, the odor containment structure is anasal mask.

As shown in FIG. 4, in a preferred embodiment the apparatus 60 includesa compressed air or gas supply 62, at least one gas filter 64, a carriermass air controller 68, a stimulus mass air controller 70, at least onestimulus odorant container (single odorant cartridge 10 or multipleodorant cartridge 11), a detector (preferably a photo ionizationdetector (PID)) 72, a mixer 74, a cartridge identifier reader 33, anactivator 31, an outlet 76 and a controller 78. In a preferredembodiment the compressed air is delivered to the at least one stimulusodorant cartridge 10 through stainless steel tubing, Teflon coated steeltubing, Teflon tubing, and/or glass tubing, and the air with odor isdelivered to the outlet 76 through stainless steel tubing, Teflon coatedsteel tubing, Teflon tubing, and/or glass tubing. In a preferredembodiment, the detector 72 measures the concentration in the cartridgeheadspace and the odorant is heated or agitated in the cartridge until aspecified odorant concentration exists in the headspace. Additionally oralternatively, the detector is incorporated into the air outlet.

The system includes four primary components that are cooperatively andoperably connected to function together under the electronic commands ofa system controller: a carrier gas dispenser, one or more odorantdispensers, an output station, and the system controller. The carriergas is air or any other suitable gas, such as nitrogen.

The carrier gas dispenser and odorant dispenser are constructed andconfigured for delivering a predetermined volume of a carrier gas or anodorant at a predetermined flow rate using a fixed-volume flowcontroller and valves.

Fixed-volume flow controller

Fixed-volume flow controllers are known in the art; basic componentsinclude a positive displacement pump, an actuator and a controller. In apreferred embodiment, the positive displacement pump is areciprocating-type positive displacement pump. By way of example and notlimitation, the positive displacement pump may be selected from thegroup consisting of a piston pump, a plunger pump, and a diaphragm pump.The positive displacement pump is connected to the motion-controlledactuator, wherein the actuator controls the displacement distance andthe displacement velocity of the piston, plunger or diaphragm with ahigh degree of precision. By controlling these two parameters, theactuator ensures that a predetermined volume of the gas is provided at apredetermined rate.

An example flow controller includes a piston pump, an actuator, aposition sensor, control valves, controller, and a power source. Thecontrol valves can be activated by pressure, mechanical force, orelectro-mechanical force. The position sensor indicates the physicalposition of the actuator and may be an encoder, potentiometer, lvdt, orany sensor capable of measuring linear position. The position sensor isread by the controller to determine position, and may be read duringmotion at known time intervals to determine velocity, acceleration, etc.Other components that can be used for alternative embodiments includeone or more humidity sensors, temperature sensors, pressure sensors, ora variety of other sensors used to identify the state of the device. Theactuator is any type of actuator that provides high accuracy, highprecision displacement distance and displacement velocity. By way ofexample and not limitation, types of actuators suitable for use with thepresent invention apparatus include hydraulic, pneumatic, electric,thermal, or magnetic (shape memory alloys), and mechanical. In oneembodiment, the actuator is a lead-screw driven by a gear-motor.

The flow-controllers contained within the device are sized so they canproduce the required flow rate for the required time at a variety ofconcentrations. Flow rate and duration are chosen such that testsubjects are presented with a sufficient volume of the mixture for asufficient time to allow for identification. Example values are a rateof 5 liters per minute for duration of 2 seconds. The flow controllersmay include additional capacity for other functions such as pre and postmixture flows and system purging.

Carrier gas assembly

The carrier gas assembly, generally shown as a carrier assembly with twoparallel chambers and plungers concentrically therewithin (“carriercylinders”), with coupled outputs 300 in FIG. 12, generates specificflow by first using pistons 312 to fill the carrier cylinders 315 withclean gas from a source. Preferably, the carrier cylinders 315 andpistons 312 are injection molded into one piece. The linear actuator 313controls the motion of the pistons. The linear actuator 313 ispreferably controlled by a controller. The controller wirelesslycontrols the linear actuator 313 remotely in one embodiment. In anotherembodiment, the controller is wired to the linear actuator 313. In oneembodiment, the system includes a V-Fill valve which is opened to createa flow path from the source (62) to either 1) a downstream module(carrier or odorant) or 2) pulled through the system by the exhaust fan(321) for purging. The fan 321 flows to the exhaust 326 and/or to thegas or air source 62, which flows to the input filter 64. Preferably,operation of the V-Fill valve is controlled by a V-Fill solenoid. Thesource is ambient air or other gas or gases. In a preferred embodiment,the air or gas(es) is filtered to remove impurities and is alsodehumidified or humidified to provide a clean gas at a predeterminedhumidity. This clean gas has two primary functions: 1) dilute theodorant to create known mixtures, and 2) purge the device to remove anyresidual odorant.

The gas filters include desiccants, such as silica gel and the like, andsorbents, such as molecular sieve materials, carbon filters,polypropylene fiber, cellulose fiber, carbon dioxide filters (KOH,NaOH), etc. The filtered air/gas is then piped directly to the carriergas assembly through a gas conduit. The carrier gas assembly withdrawscarrier gas from the gas conduit, and then injects it in arate-controlled manner into the conduit leading to the final outlet.Along the way to the final outlet, the gas is mixed with an odorant fromthe odorant assembly.

Odorant Assembly

The odorant assembly generates a volume of chemical odorant at arequested concentration and delivers that volume at a requested flowrate. Each odorant assembly includes an odorant source, such as adisposable cartridge or glass ampule, a fixed-volume flow controller,and valves to facilitate odorant generation and dispensing. In analternative embodiment, the odorant assembly includes a temperaturesensor to determine the temperature of the odorant. The odorantdispenser is connected to the carrier gas conduit in order to receivethe carrier gas for the purpose of diluting the odorant.

Preferably, the odorant cartridges, carrier chambers, and pistonsassemblies, and valves are single use, disposable, and/or injectionmolded.

An example odorant assembly is shown in FIGS. 13, 14, and 15. In FIG.13, the odorant assembly, generally described as 200, is shown with atransparent valve body. The odorant assembly includes a main inlet 201,a main outlet 203, piston 239, a piston shaft 237, a cylinder 235, alinear potentiometer 231, a balancer for offset load 233, an odorant orscent reservoir 229, a mixing chamber 205, a carrier gas inlet valve(valve A) 207, a mixture outlet valve (valve B) 209, an odor inlet valve(valve C) 211, a mixing chamber valve (valve D) 213, o-rings 215, acarrier gas inlet solenoid A 221 for controlling valve A, a mixtureoutlet solenoid B 223 for controlling valve B, an odor inlet solenoid C225 for controlling valve C, a mixing chamber outlet solenoid D 227 forcontrolling valve D. The piston, piston shaft and cylinder form thepiston assembly 238. As shown in FIG. 13, the valve configurations areset to allow carrier gas in through the odorant reservoir. Valve C 211is open, allowing carrier gas into the odorant reservoir. The valve Cincludes an o-ring 215 seal at the bottom of the scent or odorantreservoir 229 and at the top of the scent or odorant reservoir 229. Thepiston 239 is illustrated in a closed position in FIG. 13. The assemblycan include additional valves and conduits communicating with the mixingchamber to allow the odorant mixture to be routed to other devices, suchas one or more detectors.

FIG. 14 shows an odorant assembly with a transparent view of more of thecomponents of the odorant assembly. The piston 239 is illustrated in apartially retracted position in FIG. 14, allowing for a mixture ofcarrier gas and odor to fill the carrier chamber to where the piston isretracted. Valve C 211 of the odorant assembly is also open in FIG. 14.

FIG. 15 illustrates a side view of the odorant assembly showing theodorant reservoir 229 with an ultrasonic transducer 245 below the valvebody.

The operation of the odorant assembly device includes a multiplicity offunctions including, but not limited to: 1) filling with odorant, 2)filling with clean air, 3) delivering odorant to the test subject, and4) purging the system with clean air or inert gas. A detaileddescription of the interrelationship of the parts of the odorantassembly device is included below, followed by a description of thepositions of the parts of the odorant assembly when 1) filling theodorant assembly device with odorant, 2) filling with clean air, 3)delivering odorant to the test subject, and 4) purging the system withclean air or inert gas.

A main inlet or carrier gas inlet of the odorant assembly provides anopening for a tube or chamber between the carrier gas assembly and theodorant assembly. The carrier gas inlet solenoid A controls flow of thecarrier gas into the mixing chamber of the odorant assembly via thecarrier gas inlet valve (valve A). Suitable carrier gases include by wayof example and not limitation: air, nitrogen, hydrogen, and helium.Preferably, the mixture inlet valve A is open to provide a flow pathfrom to carrier source gas. Odor inlet valve (valve C) is open toprovide a flow path across the odorant reservoir and into the odorantcarrier chamber up to the point of the retracted piston. Valves B and Dare closed. Upon retraction of the odorant piston the source gas flowsinto the mixing chamber, across the odorant reservoir, and into thecarrier chamber up to the point of the piston.

In another embodiment, the mixture outlet valve (valve B) and the odorinlet valve (valve C) are in the closed position while the mixingchamber valve (valve D) is in the open position upon the carrier gasentering the mixing chamber of the odorant assembly. Upon a desired flowrate of the carrier gas being present in the mixing chamber, the odorinlet valve is moved into an open position via the odor inlet solenoidC. Preferably, the flow rate is set by the motion of the actuator anddoes not need to be measured. However, in one embodiment, the flow rateis measured at the carrier chamber or piston and in the mixing chamber.Preferably, concentration of the carrier gas does not need to bemeasured in the present invention, but is measured within the mixingchamber in one embodiment of the present invention. In anotherembodiment, the concentration of the carrier gas is measured by a singleconcentration sensor. Preferably, measurement of the concentration ofthe carrier gas is accomplished by diverting the flow of the carrier gasto the single concentration sensor, which is accomplished using aconcentration sensor valve, a concentration sensor solenoid whichcontrols the concentration sensor valve, and the single concentrationsensor.

Opening of the odor inlet valve provides for the carrier gas to enterthe scent reservoir and mix with odor from the odorant dispenser orodorant source to create a mixture of the carrier gas and the odor.Preferably, the scent reservoir includes an entrance valve with a sealand an exit valve with a seal to prevent liquid odor from spilling intovapor areas. Preferably, the odor inlet solenoid C is operable tosimultaneously open or close both the entrance valve and the exit valveto the scent reservoir. In one embodiment, the scent reservoir includesmeans to add, change, or remove an odorant, such as a closable port inthe top of the scent reservoir. A liquid or solid odorant is added orintroduced via the closable port in the top of the reservoir. In anotherembodiment, a single or multi-use replaceable cartridge containing anodorant is added via the closable port in the top of the reservoir.However, in practice a variety of techniques may be used to accomplishthis. In one embodiment, multiple scent reservoirs are utilized, eachwith a separate odor inlet valve controlled by a separate odor inletsolenoid, a separate scent reservoir exit face seal, and a separatechamber connecting the exit of the scent reservoir to the odor outletand the carrier chamber and piston assembly.

Additionally, production of odor from the odorant can be accelerated byuse of an ultrasonic transducer.

Once the carrier gas passes into the scent reservoir and mixes with theodor from the odor dispenser or the odor source, the mixture of thecarrier gas and the odor passes through the odor inlet, through thechamber between the odor inlet and the odor outlet, and through the odoroutlet. The mixture of the carrier gas and the odor then passes througha chamber connecting the odor outlet to the carrier chamber and pistonassembly. Preferably, the piston is in a closed position such that themixture of the carrier gas and the odor does not pass into the carrierchamber until activation of the piston. Upon activation (retraction) ofthe piston, the mixture of the carrier gas and the odor flows into thecarrier chamber up to the point to which the piston has been activated.The point to which the piston has been activated is preferably apredetermined distance. Preferably, the piston is retracted a specificdistance to capture a specific volume of air saturated with odorant. Inone embodiment, the predetermined distance of activation of the pistonis determined and/or implemented by a linear potentiometer. A balanceris also preferably provided to off-set the load. In another embodiment,it may be desirable to dilute the air saturated with the odorant withinthe carrier chamber up to the point of the piston. This is accomplishedby drawing additional clean air into the carrier chamber up to the pointof the piston that already contains an amount of air saturated withodorant. When filling with clean air, the V-Fill valve is opened on thecarrier gas dispenser to provide a path to clean air. Within the odorantmodule valves A and B are open while C and D are closed. The piston isretracted, drawing clean air directly into the carrier chamber up to thepoint of the piston. The piston is retracted a specific distance tocapture a specific volume of clean air.

Upon reverse activation (closing or retracting) of the piston, themixture of the carrier gas and the odor is forced from the carrierchamber and piston assembly and through the chamber connecting thecarrier chamber and piston assembly and the odor outlet. Upon opening ofthe mixture outlet valve via the mixture outlet solenoid B, the mixtureof the carrier gas and the odor passes into the mixing chamber.Preferably, opening of the mixture outlet valve and the reverseactivation of the piston is performed simultaneously. Preferably, thesystem controller includes a mechanism, which provides for simultaneousopening of the mixture outlet valve and the reverse activation of thepiston.

Upon opening of the mixing chamber valve via mixing chamber outletsolenoid D, the mixture of the carrier gas and the odor flows out of theodorant assembly. In one embodiment, the mixture outlet valve is closedbefore opening the mixing chamber valve or at the same time as openingthe mixture chamber valve. Preferably, the mixture of the carrier gasand the odor flows out of the odorant assembly and into an outputstation such as a nasal/face mask.

When delivering odorant to the test subject, the V-Fill valve ispreferably closed and the carrier chamber preferably has already beenfilled with clean air via movement of the piston. Within the odorantmodule, valve A, valve B (the mixture outlet valve), and valve D (themixing chamber valve) are open while valve C (the odor inlet valve) isclosed. The carrier piston begins to extend to start the carrier flowpassing through the odorant module's mixing chamber (flows from valve Ato D), and (at the same time or later) and odorant piston extends toinject odorant via valve B. The two flows mix are exit the mixingchamber via valve D and are delivered to the test subject.

Preferably, all valves are operable to be moved to open positions via asingle action using the system controller by activating the carrier gasinlet solenoid A, the mixture outlet solenoid B, the odor inlet solenoidC, and the mixing chamber outlet solenoid D. The single action alsocloses the piston in one embodiment. In another embodiment, the singleaction opens the piston. The single action using the system controlleris preferably automated. In another embodiment, the single action usingthe system controller is provided or activated when a button ispositioned in a depressed position the system controller. However, in apreferred embodiment of the present invention, user-initiated actionsvia pressing of a button or performing any other action through aphysical or electronic interface, including a Graphical User Interface(GUI) is performed only for beginning or starting or initiating themethods of the present invention and for identifying an odorant by theparticipant. Opening all the valves and opening and/or closing of thepiston provides for a carrier gas to purge the odorant assembly of anyresidual odors.

When purging the mixing chamber, the V-Fill valve is closed and thecarrier chamber and piston assembly has already been filled with cleanair. Within the odorant module valves A and D are open, and B and C areclosed. The carrier piston extends pushing clean air through the mixingchamber, forcing any residual odorant out via valve D.

In another embodiment, purging is accomplished by opening the V-Fillvalve, opening valves A and D for one or more of the odorant modules,and turning on the fan (321) to pull clean air through the system(purge). Preferably the system includes a bypass for the output mask sono purge air is presented to the test subject.

When purging the odorant carrier chamber and piston assembly, the stepof filling with clean air procedure is followed or repeated one or moretimes.

When purging the odorant reservoir, the odorant carrier chamber andpiston assembly is filled with clean air or inert gas from a separatesource. Valves C and D are open, and valves A and B are closed. Theodorant piston is extended, pushing air through the odorant reservoirand out via valve D.

Thus, exemplary valve states for different operations are summarized asfollows. Filling the carrier chamber and piston assembly with odorant:V-Fill open, A open, B closed, C open, D closed, retract piston. Fillingthe carrier chamber and piston assembly with clean air: V-Fill open, Aopen, B open, C closed, D closed, retract piston. Filling the carrierchamber and piston assembly with clean air is performed after fillingthe piston with odorant to dilute the odorant within the carrier chamberin one embodiment. Delivering odorant (mix): V-Fill closed, A open, Bopen, C closed, D open, start carrier flow, extend piston. Purging themixing chamber: V-Fill closed, A open, B closed, C closed, D open, startcarrier flow. Purging the odorant reservoir: fill odorant carrierchamber and piston assembly with clean air or inert gas (such asnitrogen, not shown), V-Fill closed, A closed, B closed, C open, D open,extend piston. Delivering the odorant (no mix): V-Fill closed, A closed,B open, C closed, D open, extend piston.

The odorant source contains the volatile chemical(s) of interest, mostoften in a liquid form, although a compressed gas form is provided forherein; and can be pure or diluted in another substance, such as water,diethyl phthalate, mineral oil, another carrier gas in the case of acompressed gas form, etc. The odorant source may be intended for singleuse or multiple uses. In preparation for mixture creation, some of thechemical source is converted from liquid to vapor. This conversion maybe natural (diffusion) or accelerated through artificial means, such asultrasonic vibration, heat, and the like. The conversion is designed tocreate a known volume of a known concentration of the odorant vapor.This is accomplished by the following steps:

1) Calculating the expected vapor pressure of the chemical usingenvironmental conditions (temperature, humidity, etc.) and expectedvapor pressure of any present diluent.2) Exposing the chemical to a clean gas to provide for its diffusioninto the clean gas.3) Accelerating the diffusion using a catalyst or a catalytic action, byway of example and not limitation, using ultrasonic vibration, heat,etc., for producing an odorant at the chemical's vapor pressure(saturated odorant), and any excess chemical remains in liquid form,thus providing the chemical odorant at a known concentration.4) Retracting the odorant dispenser's piston or actuator a specific orpredetermined distance to draw the saturated odorant into the carrierchamber up to the point of the piston, thereby obtaining a specificvolume of the chemical at the known vapor pressure.5) Optionally filling the odorant disperser's carrier chamber and pistonassembly with additional clean air to dilute the saturated odorant priorto mixing with the carrier stream. This may be done to improve accuracyof the mixture when producing relatively low concentrations. For exampleif the required concentration needs the odorant dispenser's carrierchamber and piston assembly to be filled with 10% saturated odorant, theremaining 90% may be filled with clean air, to allow utilization of thefull range of travel of the odorant piston in order to improve movementaccuracy. In this case the carrier stream flow rate would be adjusted tocompensate for the additional dilution.

The odorant generated by this process represents the highestconcentration of the chemical that may be achieved, limited by thephysical properties of the chemical and the environmental conditions.

Mixing

The odorant vapor thus formed is mixed with clean gas to producemixtures of lower concentration. Precise mixtures are created bydispensing the odorant vapor and clean carrier gas at specific rates andmixing their outputs.

Mixtures are created by the following steps:

1) Generating an odorant vapor and filling the odorant dispenser2) Filling a clean gas dispenser3) Calculating the required flow-controller speeds to generate thedesired odorant/carrier gas ratio. For example:

a. Target is a 25% mixture of chemical A.

b. Calculate the vapor pressure of chemical A at the currentenvironmental conditions, and determine that it will yield a 50% mixturein the odorant dispenser.

c. Given the odorant % and the target%, the flow ratio may be calculatedby

-   -   i. r_(flow)=(p_(odorant)/p_(target))−1    -   ii. r_(flow)=(50%/25%)−1    -   iii. r_(flow)=1

d. This means the clean gas flow rate should equal the odorant flowrate.

e. Given the total flow rate, calculate the flow rates for the carriergas and the odorant vapor.

4) Moving both flow controllers simultaneously and at the calculatedflow rate ratio to mix the odorant and the carrier gas.5) Mixing the flows from both controllers to create the desired mixture.

Output station

The output station delivers the mixture to a test subject and includessystems and devices to capture subject feedback. The feedback methodsinclude any of those known in the art, including touchscreens,keyboards, voice recorders, and the like. In an example embodiment forhuman odor testing and analysis, the output station is a nasal/face maskand the feedback capture device is a touchscreen on which thesubject/patient reports odorant detection, or a microphone, into whichthe test subject speaks to identify the presence and characteristics ofthe one or more odors being delivered through the mask.

Detector

In one embodiment, the system includes an odorant detector, whichdetects and measures odorant levels in the carrier gas and transmits thedata to the controller. The detector is preferably a photoionizationdetector, although any detector suitable for detecting volatile chemicalvapors in a gaseous mixture can be used. In a preferred embodiment, thetheoretical carrier gas concentration is calculated based on thechemical physical properties and environmental conditions, and thusadvantageously no detector is needed.

System controller

The system controller controls operation of the device. The primaryfunction of the controller is to run one or more test sequences, whereodorants of various concentrations are delivered to a test subject andthe subject's feedback is collected and stored. In addition thecontroller is responsible for maintenance functions such as systemdiagnostics, cleaning, and communication of results.

During odorant mixture generation and delivery the system controlleroperates the various system components (valves, actuators, etc.) toproduce the desired results. For mixing, the controller first calculatesthe speeds of the carrier and odorant actuators to produce the desiredmixture and then drives the actuators at speeds to produce the desiredmixture at the desired flow rate. Actuator motion may be controlled by avariety of closed-loop motion control schemes, such asproportional-integral-derivative control (PID-control), which utilizethe feedback of the actuator's position sensor to precisely controlmotion.

The mixture concentration is determined by the relative flows of eachactuator which is proportional to their actuation speed. The total flowrate is the sum of the flows of each active actuator.

A system according to the present invention, generally described as 100in FIG. 16, includes a gas source and exhaust 20, one or more odorantdispensers 200, 240, 250, 260, a system controller 78, and an outputstation 76. Additional elements include a mixing chamber 205, aphotoionization detector (PID) 72 and output filter 120.

Operational sequences

Methods for operating the present invention include the steps of:dispensing an odorant mixture, capturing test subject feedback inresponse to being presented with a mixture, purging the system ofodorants, and system diagnostics and maintenance.

The method steps for dispensing an odorant mixture, using the schematicsystem illustrated in FIG. 16, are as follows:

A) Filling the Carrier-Gas Dispenser 300:

1) Opening the valve V-Fill 224

2) Retracting the Clean-Air Dispenser, fill path is 1) Ambient Gas orAir 62, Input Filter 64, V-Fill 224, Clean-Air Dispenser 300.

B) Filling the Odorant Dispenser 200 with Odorant:

1) Opening valve V-Fill 224

2) Energizing the Ultrasonic Vibrator 245

3) Opening valve V-Odorant 211

4) Opening valve V-In 207

5) Retracting Odorant Dispenser Piston Assembly 238, fill path is 1)Ambient Air 62, Input Filter 64, V-Fill 224, V-In 207, V-Odorant 211(including Odorant Reservoir 229), Odorant Piston/Cylinder Chamber

C) Delivering the Mixture to the Output Station 76:

1) Filling Clean-Air Dispenser 25 and Odorant Dispenser Piston/CylinderChamber as described above

2) Closing the valve V-Fill 224

3) Opening the valve V-In 207

4) Opening the valve V-Carrier Chamber 209

5) Opening the valve V-Output Station 213

6) Extending Clear-Air Dispenser and Odorant Dispenser simultaneously,flow paths are:

(a) Clean-Carrier Gas: Clean-Carrier Gas Dispenser 300 (Piston Chamber),V-In 207, Mixing chamber 205, V-Output Station 213, Output Station 76

(b) Odorant: Odorant dispenser piston assembly 238, V-Carrier chamber209, Mixing chamber 205, V-Output Station 213, Output Station 76.

To deliver the odorant/gas mixture to the PID for calibration, the pathsfrom the Mixing Chamber are as follows: V-Measure 247, PID 72.

To deliver the odorant/gas mixture simultaneously to the Output Stationand PID, the paths from the Mixing Chamber are as follows: V-OutputStation-213 and V-Measure 247, then Output Station 76 and PID 72.

Excess carrier gas or purging carrier gas flows from the fan 321 to 62gas or air and/or 326 exhaust.

Multiple Odorant Mixtures, Delayed Onset and Masking of Changes

The system is also configured to provide multiple odorantssimultaneously or sequentially. When mixing multiple odorants, thesystem controller provides for adjusting the carrier gas and individualodorant flows so that the maximum system flow capacity is not exceededand the multiple odorants are at the desired concentrations.

The system also provides for sequential or delayed addition of odorantsto the carrier gas. By way of example and not limitation, a second odoris added one (1) second after the first odor was introduced into thecarrier gas.

In some cases, it is desirable to mask certain changes in the deviceoperation from the test subject, in order to prevent the subject frommaking guesses as to when certain events occur, such as the start of anodorant flow or the addition of a secondary odorant. Changes may beinadvertently communicated to the test subject via changes in air flow,changes in sound, etc. Techniques to mask such changes may includeconcealment or misdirection. Concealment examples include 1) precisecontrol over component flows (carrier and odorants) so the total flowrate does not change, for example as a first component flow increases asecond component flow decreases at the same rate to maintain aconsistent total; and 2) using silent actuators or sound insulation toprevent the test subject from hearing the internal operations of thedevice. Misdirection examples include 1) deliberate inconsistency in theodorant flow (pulsing) so changes are not distinguishable or 2)including a placebo flow which does not contain any particular odorant,while maintaining the same operation as the real odorants.

By way of example and not limitation, for the compressed air supply, adisposable compressed air volume (e.g., CO2 cartridge) or a small, quietair pump is used. The apparatus is computer-controlled either directlythrough the controller 78 or remotely controlled via network-basedcommunication.

In an alternative embodiment shown in FIG. 5, an extra headspacecartridge or reservoir 13 is used to provide extra headspace. Airflowthrough the odorant cartridge is routed to the extra headspacecartridge. When a test is actuated, the test air is taken from the extraheadspace cartridge. Between tests the air is recirculated between theodorant cartridge and extra headspace cartridge to ensure theappropriate concentration of odor in the extra headspace cartridge.

The compressed air is channeled through the at least one odorantcontainer, which is directed into the disposable or replaceableheadspace reservoir 13 then mixed with an appropriate amount of morecarrier air and sent to the mixer 74. As the stimulus air leaves theodorant container or extra headspace cartridge, the detector 72determines if the required amount of odor is contained in the stimulusair. In the mixer, multiple stimuli odors are mixed and then sent to theoutput. Alternatively, fresh filtered air is pumped and channeledthrough the at least one odorant container.

The apparatus preferably includes an input device 82, such as atouchscreen, whereby the test administrator, the person being testedand/or other user input information, including demographic, medical,genetic, lifestyle information and the like.

The input device also provides for allowing the different users to shareother database data, including social media databases, medicaldatabases, genetic databases, genealogical databases, cognitive testing(e.g., Lumosity.com) databases and the like, which are uploaded to thesystem database.

Odorants may be sticky and adhere to the air flow channels, thus affectconcentrations of tests. Sticking or fouling is prevented by a number ofpossible options, including use of concentric tubing arrangements wherethe odorant is presented from the center tube, into an airflow fromlarger surrounding tubes close to the point of emission into the area ofdetection testing. Desorption of air channels can also be provided byheating delivery tubing at high temperatures. For example, the airchannels are stainless steel tubes, and are heated after a test to burnoff the fouling odorant(s). Alternatively, the tubing between thecartridge and emission is designed and constructed to be easilychangeable and inexpensive. Preferably, the tubing is operable to becleaned for reuse or is disposable.

The apparatus includes detectors that can measure vapor concentrationthrough such mechanisms as photoionization, thermal conductivity, chargedetection, infrared absorption, etc. The apparatus then correspondinglyalters the ratio of carrier air mixed with the cartridge effluent air,postpones a test, or alerts a test administrator so that only propertests are performed. Preferably, the detector can detect theconcentration of the odor in the air stream and vary the ratio ofcarrier air to sample air to achieve the desired concentration.Detectors include PID, charge detectors, other spectroscopy detectorsand/or conductance detectors. Preferably, each cartridge automaticallyruns an initial calibration before testing begins. By way of example andnot limitation, the cartridge is inserted, calibration is automaticallyperformed, and testing is ready. Additionally, a control cartridge forcalibrating an apparatus is provided.

The outlet preferably includes an odor containment structure, such as afunnel, nasal mask or sniff port for confining the odor such that it isnot diluted by air currents. The person places his or her nose in thenasal mask to sense the odor. In a preferred embodiment, a photobeam isdirected across the entrance of the odor containment structure, and whenthe person interrupts the photobeam, the tester emits the odor throughan odor tube into the odor containment structure.

The present invention reduces the cost of testing humans for olfactoryabilities through various ways. For example, the odorant cartridges aredisposable, which allows proper standardization between cartridges andolfactometers so that the system and methods for testing arestandardized. Furthermore, the testing time is decreased because thepresent invention increases the testing rate and reduces the preparationtime, error rate and cleanup time versus prior art methods.

System for assessing olfactory system odor detection ability to predictcognitive impairment and health conditions such as diabetes, exposuresto toxins, allergies, and/or idiopathic conditions and diseases.

The present invention provides for a system, generally described as 800in FIGS. 6, 9 and 10, for testing and validating the smelling ability ofhumans. The system includes at least one tester apparatus 60 incommunication through a wired or wireless electronic network 810 with aserver 850. In one embodiment, the tester is not necessary to thefunction of the system as the apparatus controls itself or testing andvalidating is performed remotely. The server is in communication with apopulation database 870 of test results. Preferably, the populationdatabase 870 of test results includes previous longitudinal olfactorymeasures from the same individual. The system preferably provides forseveral or numerous tester apparatuses to independently transmit testresults to the server. The server compares received results to theprevious results for that patient and/or to the population database andalso updates the population database with the results. The comparedresults, shown in FIG. 7, are transmitted back to the tester or localcomputing device associated with the tester. This real-time ornear-real-time analysis and reporting of data enables the rapidscreening, assessment, and comparison of test subjects. Furthermore, thesystem transmits new programs and stimulus conditions to testers.

The present invention also provides for semi-autonomous administrationof tests, wherein the apparatus is able to provide tests withoutconnection to a server, but once the apparatus is in networkcommunication with the server, the test data are uploaded and analysisperformed at the server.

In another embodiment, the apparatus is a remote-controlled device,wherein the tests are administered from a remote location. In theseembodiments, the test administrators can instruct the person beingtested via GUI or voice instructions, or conduct the test automaticallywith the patient or subject without input from a local administrator.

Database

In a preferred system, the assessments are more valid and reliable whenthe instant scores or results are compared against a population databaseof standardized test results. Preferably, the population database is ademographically appropriate database selected from an overall populationdatabase. The comparison may be limited to assessments of the individualin past tests or limited to assessments of family members of theindividual in past tests. This provides for longitudinal testing. In oneembodiment, the population database of test results includes demographicsub-populations, wherein the assessments of the instant scores orresults are compared against one or more relevant demographicsub-populations. Preferably, the demographic sub-populations areconstructed by age, weight, gender, socioeconomic status, ethnicity,height, genetic predispositions, existing health conditions, andcombinations thereof. Preferably, the instant results populate and growthe database to further enhance the reliability of the populationdatabase. Preferably, the instant results are validated or verifiedprior to being incorporated in the database. The database containspopulation distributions, such as shown in FIG. 8, for a variety ofodorants, such as, by way of example and not limitation, pure compounds,compound mixtures, masking compounds and masking mixtures. Preferably,common odorants such as rose, clove, eucalyptus, and lemon are used forodor identification, with pure odorants being used for sensitivity. Forexample, a population distribution exists for methanol, butanol, ormethanol and butanol mixed. Significantly, the device of the presentinvention affords standardized quantifiable data so assessmentverification can be performed.

Preferably, the population database only includes dynamic, collectedpopulation data. The dynamic, real-time updating of the databaseprovides for testing against the most current data. Furthermore, changesin populations can also be tracked over time with the present invention.Thus, not only can individuals be compared to populations, but cohortpopulations can also be compared to previous populations to see if thepopulation is varying.

Alternatively, test comparisons are initially performed using variancesor estimated standards. A database for the new population issimultaneously populated with data collected via testing until a givennumber of records populate the database, at which point the comparisonsare performed against the database of collected population data.

Also alternatively, the testing is started without standards and thecomparisons are performed after a sufficient number of persons aretested to create a population variance.

A population database according to the present invention includes, byway of example and not limitation, demographic, medical, andoccupational variables of humans. Demographic variables include race,age, marital status, occupation, income, religion, residence, ethnicity,diet and sex. Medical variables include existing co-morbidities, familyhistory, medications and genetics. Occupational variables include sportand chemical exposure. Other database that can be used include geneticdatabases, genealogical databases, and cognitive testing (Lumosity.com)databases.

Another database embodiment provides for a database that containspopulation distributions for any olfactory test with any pure compoundor compound mixture based on where in the olfactory system anatomy theyare tested: the receptor, olfactory bulb, or piriform cortex, and/orprefrontal cortex. In general, the present invention provides foraddressing disease processes and injury at different locations in theolfactory nervous system pathway, for example, but not limited to inodor detection in the olfactory epithelium (with olfactory sensoryneurons), odor discrimination in the olfactory bulb, odor identificationin the piriform cortex and odor adaptation in the epithelium.

For example, a pure monomolecular chemical, such as methanol, has apopulation distribution for detection, threshold testing, and/or overallsensitivity testing at the receptor, whereas a mixed compound, such asmethanol and butanol, has a population distribution for testing anddiscrimination at the olfactory bulb.

Odorants include complex odorants that include more than one odorant,such as, by way of example and not limitation, natural odorants such ascoffee, grass, gas, and the like.

Another embodiment provides for a database that contains populationdistributions developed from odorant testing of a compound specific toan odor sensing nerve type, wherein the compound is pure, mixed, ormasking and the nerve type is olfactory (CN1) or trigeminal (CN5).

Another embodiment provides for a database that contains populationdistributions developed from odorant adaptation, wherein thedistribution is time-to-adaptation for specific pure or mixedcompound(s).

In a preferred embodiment, the population distributions within apopulation database are normalized. By way of example and notlimitation, a normal distribution is z-score normalized. Thisnormalization allows test scores to be compared against the variance ofthe population, thereby confirming where in the population the personlies. In another embodiment, the population database is a population ofabsolute and relative concentration values. In yet another embodiment, aseparate population database exists for absolute and normalizedpopulations.

Computing system

FIG. 10 is a schematic diagram of an embodiment of the inventionillustrating a computer system, generally described as 800, having anetwork 810, a plurality of computing devices 820, 830, 840, a server850 and a database 870.

The server 850 is constructed, configured and coupled to enablecommunication over a network 810 with a computing devices 820, 830, 840.The server 850 includes a processing unit 851 with an operating system852. The operating system 852 enables the server 850 to communicatethrough network 810 with the remote, distributed user devices. Database870 may house an operating system 872, memory 874, and programs 876.

In one embodiment of the invention, the system 800 includes acloud-based network 810 for distributed communication via a wirelesscommunication antenna 812 and processing by a plurality of mobilecommunication computing devices 830. In another embodiment of theinvention, the system 800 is a virtualized computing system capable ofexecuting any or all aspects of software and/or application componentspresented herein on the computing devices 820, 830, 840. In certainaspects, the computer system 800 may be implemented using hardware or acombination of software and hardware, either in a dedicated computingdevice, or integrated into another entity, or distributed acrossmultiple entities or computing devices.

By way of example, and not limitation, the computing devices 820, 830,840 are intended to represent various forms of digital computers 820,840, 850 and mobile devices 830, such as a server, blade server,mainframe, mobile phone, a personal digital assistant (PDA), a smartphone, a desktop computer, a netbook computer, a tablet computer, aworkstation, a laptop, and other similar computing devices. Thecomponents shown here, their connections and relationships, and theirfunctions, are meant to be exemplary only, and are not meant to limitimplementations of the invention described and/or claimed in thisdocument

In one embodiment, the computing device 820 includes components such asa processor 860, a system memory 862 having a random access memory (RAM)864 and a read-only memory (ROM) 866, and a system bus 868 that couplesthe memory 862 to the processor 860. In another embodiment, thecomputing device 830 may additionally include components such as astorage device 890 for storing the operating system 892 and one or moreapplication programs 894, a network interface unit 896, and/or aninput/output controller 898. Each of the components may be coupled toeach other through at least one bus 868. The input/output controller 898may receive and process input from, or provide output to, a number ofother devices 899, including, but not limited to, alphanumeric inputdevices, mice, electronic styluses, display units, touch screens, signalgeneration devices (e.g., speakers) or printers.

By way of example, and not limitation, the processor 860 may be ageneral-purpose microprocessor (e.g., a central processing unit (CPU)),a graphics processing unit (GPU), a microcontroller, a Digital SignalProcessor (DSP), an Application Specific Integrated Circuit (ASIC), aField Programmable Gate Array (FPGA), a Programmable Logic Device (PLD),a controller, a state machine, gated or transistor logic, discretehardware components, or any other suitable entity or combinationsthereof that can perform calculations, process instructions forexecution, and/or other manipulations of information.

In another implementation, shown as 840 in FIG. 10, multiple processors860 and/or multiple buses 868 may be used, as appropriate, along withmultiple memories 862 of multiple types (e.g., a combination of a DSPand a microprocessor, a plurality of microprocessors, one or moremicroprocessors in conjunction with a DSP core).

Also, multiple computing devices may be connected, with each deviceproviding portions of the necessary operations (e.g., a server bank, agroup of blade servers, or a multi-processor system). Alternatively,some steps or methods may be performed by circuitry that is specific toa given function.

According to various embodiments, the computer system 800 may operate ina networked environment using logical connections to local and/or remotecomputing devices 820, 830, 840, 850 through a network 810. A computingdevice 830 may connect to a network 810 through a network interface unit896 connected to the bus 868. Computing devices may communicatecommunication media through wired networks, direct-wired connections orwirelessly such as acoustic, RF or infrared through an antenna 897 incommunication with the network antenna 812 and the network interfaceunit 896 , which may include digital signal processing circuitry whennecessary. The network interface unit 896 may provide for communicationsunder various modes or protocols.

In one or more exemplary aspects, the instructions may be implemented inhardware, software, firmware, or any combinations thereof. A computerreadable medium may provide volatile or non-volatile storage for one ormore sets of instructions, such as operating systems, data structures,program modules, applications or other data embodying any one or more ofthe methodologies or functions described herein. The computer readablemedium may include the memory 862, the processor 860, and/or the storagemedia 890 and may be a single medium or multiple media (e.g., acentralized or distributed computer system) that store the one or moresets of instructions 900. Non-transitory computer readable mediaincludes all computer readable media, with the sole exception being atransitory, propagating signal per se. The instructions 900 may furtherbe transmitted or received over the network 810 via the networkinterface unit 896 as communication media, which may include a modulateddata signal such as a carrier wave or other transport mechanism andincludes any delivery media. The term “modulated data signal” means asignal that has one or more of its characteristics changed or set in amanner as to encode information in the signal.

Storage devices 890 and memory 862 include, but are not limited to,volatile and non-volatile media such as cache, RAM, ROM, EPROM, EEPROM,FLASH memory or other solid state memory technology, disks or discs(e.g., digital versatile disks (DVD), HD-DVD, BLU-RAY, compact disc(CD), CD-ROM, floppy disc) or other optical storage, magnetic cassettes,magnetic tape, magnetic disk storage or other magnetic storage devices,or any other medium that can be used to store the computer readableinstructions and which can be accessed by the computer system 800.

It is also contemplated that the computer system 800 may not include allof the components shown in FIG. 10, may include other components thatare not explicitly shown in FIG. 10, or may utilize an architecturecompletely different than that shown in FIG. 10. The variousillustrative logical blocks, modules, elements, circuits, and algorithmsdescribed in connection with the embodiments disclosed herein may beimplemented as electronic hardware, computer software, or combinationsof both. To clearly illustrate this interchangeability of hardware andsoftware, various illustrative components, blocks, modules, circuits,and steps have been described above generally in terms of theirfunctionality. Whether such functionality is implemented as hardware orsoftware depends upon the particular application and design constraintsimposed on the overall system. Skilled artisans may implement thedescribed functionality in varying ways for each particular application(e.g., arranged in a different order or partitioned in a different way),but such implementation decisions should not be interpreted as causing adeparture from the scope of the present invention.

By way of definition and description supporting the claimed subjectmatter, preferably, the present invention includes communicationmethodologies for transmitting data, data packets, messages or messagingvia a communication layer. Wireless communications over a network arepreferred. Correspondingly, and consistent with the communicationmethodologies for transmitting data or messaging according to thepresent invention, as used throughout this specification, figures andclaims, wireless communication is provided by any reasonable protocol orapproach, by way of example and not limitation, Bluetooth, Wi-Fi,cellular, zigbee, near field communication, and the like; the term“ZigBee” refers to any wireless communication protocol adopted by theInstitute of Electronics & Electrical Engineers (IEEE) according tostandard 802.15.4 or any successor standard(s), the term “Wi-Fi” refersto any communication protocol adopted by the IEEE under standard 802.11or any successor standard(s), the term “WiMax” refers to anycommunication protocol adopted by the IEEE under standard 802.16 or anysuccessor standard(s), and the term “Bluetooth” refers to anyshort-range communication protocol implementing IEEE standard 802.15.1or any successor standard(s). Additionally or alternatively to WiMax,other communications protocols may be used, including but not limited toa “1G” wireless protocol such as analog wireless transmission, firstgeneration standards based (IEEE, ITU or other recognized worldcommunications standard), a “2G” standards based protocol such as “EDGEor CDMA 2000 also known as 1XRTT”, a 3G based standard such as “HighSpeed Packet Access (HSPA) or Evolution for Data Only (EVDO), anyaccepted 4G standard such as “IEEE, ITU standards that include WiMax,Long Term Evolution “LTE” and its derivative standards, any Ethernetsolution wireless or wired, or any proprietary wireless or power linecarrier standards that communicate to a client device or anycontrollable device that sends and receives an IP based message. Theterm “High Speed Packet Data Access (HSPA)” refers to any communicationprotocol adopted by the International Telecommunication Union (ITU) oranother mobile telecommunications standards body referring to theevolution of the Global System for Mobile Communications (GSM) standardbeyond its third generation Universal Mobile Telecommunications System(UMTS) protocols. The term “Long Term Evolution (LTE)” refers to anycommunication protocol adopted by the ITU or another mobiletelecommunications standards body referring to the evolution ofGSM-based networks to voice, video and data standards anticipated to bereplacement protocols for HSPA. The term “Code Division Multiple Access(CDMA) Evolution Date-Optimized (EVDO) Revision A (CDMA EVDO Rev. A)”refers to the communication protocol adopted by the ITU under standardnumber TIA-856 Rev. A.

It will be appreciated that embodiments of the invention describedherein may be comprised of one or more conventional processors andunique stored program instructions that control the one or moreprocessors to implement, in conjunction with certain non-processorcircuits, some, most, or all of the functions for the systems andmethods as described herein. The non-processor circuits may include, butare not limited to, radio receivers, radio transmitters, antennas,modems, signal drivers, clock circuits, power source circuits, relays,current sensors, and user input devices. As such, these functions may beinterpreted as steps of a method to distribute information and controlsignals between devices. Alternatively, some or all functions could beimplemented by a state machine that has no stored program instructions,or in one or more application specific integrated circuits (ASICs), inwhich each function or some combinations of functions are implemented ascustom logic. Of course, a combination of the two approaches could beused. Thus, methods and means for these functions have been describedherein. Further, it is expected that one of ordinary skill in the art,notwithstanding possibly significant effort and many design choicesmotivated by, for example, available time, current technology, andeconomic considerations, when guided by the concepts and principlesdisclosed herein, will be readily capable of generating such softwareinstructions, programs and integrated circuits (ICs), and appropriatelyarranging and functionally integrating such non-processor circuits,without undue experimentation.

Analyses

Together, these variables are analyzed to identify health conditions orto predict a person's risk of cognitive decline. An olfactory functionassessment is performed and the results compared against an appropriatepopulation database. By way of example and not limitation, a 60-year oldfemale would be assessed on her odor detection ability ofcinnamaldehyde. Her quantified ability to detect a given concentrationof cinnamaldehyde would be analyzed and compared against other 60-yearold females, her own threshold at a younger age, and/or a combination ofother 60-year old females, the 60-year old females' threshold at ayounger age, and her own threshold at a younger age. The analysis isselected from, by way of example and not limitation, discriminate,regression, or mixed model, and the comparison appears as, by way ofexample and not limitation, a percent rank or variance from thepopulation mean.

In a preferred embodiment individual olfactory measures for odordetection/sensitivity, odor identification, odor discrimination, andodor adaptation are compared with longitudinal results from the sameindividual or from the same demographic comparison group to compute anumerical metric of function (Olfaxis Index). Thus, a variety of OlfaxisIndices are preferably utilized in the present invention: sensitivitymetric (S-Olfaxis Index), odor identification metric (ID-Olfaxis Index),an individual sensitivity metric (Ind-Sensitivity Olfaxis Index), athreshold metric (T-Olfaxis Index), etc. These metrics are preferablyused to determine functional status.

Preferably, the odor identification metric (ID-Olfaxis Index), oridentification performance, is measured by presenting between a minimumof 6 individual odors and a maximum of 25 individual odors to theindividual. Preferably, the individual is given a list of possible odorsto choose from for each individual odor presented to the individualuser. In one embodiment, the list is a list of 4 possible odors. Inanother embodiment, the individual is not given a list of possible odorsto choose from. In one embodiment, a plurality of odors is mixed and theindividual identifies as many of the plurality of odors in the odormixture as possible.

In one embodiment, assessment to obtain data for calculating asensitivity metric (S-Olfaxis Index), an individual sensitivity metric(Ind-Sensitivity Olfaxis Index), and/or a threshold metric (T-OlfaxisIndex) is performed by testing an individual at a high concentration ofan odorant in a carrier gas and lowering the concentration of theodorant in the carrier gas serially through repeated tests until theindividual does not recognize that an odorant is present or until theindividual cannot identify the odor produced by the odorant. In anotherembodiment, an assessment is performed by testing an individual at a lowconcentration of an odorant in a carrier gas and raising theconcentration of the odorant in the carrier gas serially throughrepeated tests until the individual recognizes that an odorant ispresent or until the individual can identify the odor produced by theodorant. In yet another embodiment, an assessment is performed using oneor more odorants at standard or predetermined concentrations and anindividual is asked to identify the odor produced from the one or moreodorants. Preferably, the individual is given a list of odors to choosethe one or more odorants from.

A given assessment preferably reveals where a person fits on at leastone cohort or otherwise related population distribution. A given set oflongitudinal assessments, wherein longitudinal assessments are more thanone assessment over time, reveal how the olfactory functions of a personcompares to appropriate populations for a given odor over a given periodof time.

In one embodiment, an Olfaxis Index is calculated by dividing dataobtained from a current assessment of an individual to data obtained bya past assessment of the individual or by data obtained by pastassessments of a suitable normalized population distribution. In oneembodiment, the data is a minimum concentration of odorant in a carriergas necessary to obtain a positive response from the individual. Inanother embodiment, the data is the number of odors correctly identifiedby the individual. In another embodiment, the data is a percentage ofodors correctly identified by the individual. In one embodiment, thepositive response is an acknowledgment of a presence of an odor. Inanother embodiment, the positive response is an identification of theodor present.

An individual's threshold metric is preferably calculated by giving anassessment to the individual for his or her smelling ability andcomparing the assessment of the individual to one or more pastassessments of the individual and/or to past assessments of a suitabledemographic population. For example, an individual receives anassessment for his or her smelling ability, wherein the analysis andresults reveal that individual's threshold sensitivity is four times themean of the appropriate normalized population distribution, yielding ametric (Olfaxis Index) of 0.25. If in a set of longitudinal assessmentsthat individual continues to score an Olfaxis Index of 0.25, or for anexample 2 standard deviations below the mean, then further medical orcognitive examination may not be warranted, because the individual onlyhas a poor odor detection ability without predicted cognitive decline.Preferably, this analysis is automated.

In another example, if individual A had odor sensitivity measured today,his performance could be compared with the same measure made 12 monthsago. If the measures are the same, his sensitivity metric (S-OlfaxisIndex would be 1.0). If his odor sensitivity for the same odorant wasdecreased, and his threshold was twice what it was 1 year ago, hissensitvity metric (S-Olfaxis Index) for the odorant would be 0.5.

In yet another example, if individual A had odor identificationperformance measured today, his performance could be compared with thesame measure made 12 months ago. If the measures are the same, his odoridentification metric (ID-Olfaxis Index would be 1.0). If his ID forsame odorant was decreased, and his odor ID score was half what it was 1year ago, his odor ID metric (ID-Olfaxis Index) for the odorant would be0.5.

In another example, if the individual has undergone a single olfactorytest, the results are preferably compared against the database forappropriate demographic population. If the individual's thresholds arethree times higher than the comparison demographic threshold, the metric(Ind-Sensitivity Olfaxis Index) will be 0.333.

In another example, an individual's threshold for two odorants might bequantitatively compared to compute an objective metric of function. Inthis embodiment, an odorant that activates the trigeminal nerve (ex:carbon dioxide) might be used as a standard, against which changes inolfactory nerve function (ex: for vanillin odorant) might be quantified(T-Olfaxis Index).

In another embodiment, an individual's performance on differentolfactory tests constructed to measure olfactory performance atdifferent levels within the olfactory central nervous system might becompared to identify the pathological brain region. Odor thresholds mayreflect the functional status of olfactory receptors in the olfactoryepithelium. Olfactory discrimination measures may reflect functionalcondition of the olfactory bulb. Odor adaptation measures function ofthe olfactory receptor in the epithelium and in the piriform cortex.Olfactory identification measures may reflect functional condition ofthe piriform cortex or prefrontal cortex.

Comparison of each of these measures with comparable measures from theappropriate demographic population would generate a metric indicatingthe level in the central nervous system affected by mental/physicalhealth problems or neurological disorder. For example, if odor thresholdwas normal (Olfaxis Index of 1.0), and odor discrimination had anOlfaxis Index of 1.0, but Odor ID had an Olfaxis Index of 0.2, then theindividual might be referred for MRI and cognitive testing.

A decline in odor detection ability is known to accompany physiologicalageing, senility, and other health conditions. Therefore, a set ofpopulation distributions within the population database would reveal ahyposmic shift with age of a specific population, such as male, awayfrom a normal or pre-senile population. This hyposmic shift would happenat a mean rate over a given set of years: The hyposmic shift in 10-yearincrements reveals ageing population progression below the normal,pre-senile population mean as shown in FIG. 8, for example, at 40, 50,and 60 years of age. This rate of physiological decline is preferablyassessed for a number of odorants.

However, if in an example set of longitudinal assessments that sameindividual progressively scores 0.8, 1.0, 1.2, and 1.5 standarddeviations below the mean for a cohort or otherwise appropriatepopulation, then further cognitive examination or health evaluation maybe warranted, since declining odor detection ability relative to anappropriate population is strongly correlated with cognitive decline.Evaluating how an individual person's odor detection ability changesover time relative to the population is more important for the purposesof predicting cognitive decline than how that individual compares to agiven population at a given time.

A comparison against the physiological ageing decline in odor detectionof a given odor or mixture of odors is thus used to detect a decline inpathological odor detection. For example, as shown in FIG. 7A-C, if theindividual's results 71 shift hyposmically at a faster rate than that ofphysiological ageing (independent of initial assessment), then apreliminary diagnosis of cognitive decline is made.

Analysis of the combined population database and the medical history ofthe testers provides for the identification of predictive orpathognomonic odor losses or patterns of odor losses. These odors canthen be used in early-screening tests to reverse, prevent, or slow downdisease progression.

Reaction time (RT) can also be used as an indicator of stimulussalience. For example, if the concentration is very high and thereforevery obvious or salient to the animal/person, the reaction time is verybrief If the concentration is very low and near threshold, the reactiontime is relatively long. Therefore, the detector is designed,configured, and constructed to measure the reaction time of the testsubject.

Olfactory Pathway Analysis

A preferred use of the present system is determining where in theolfactory system pathway a decline in odor detection, adaptation,discrimination and/or identification exists. The olfactory systempathway consists of receptors at the epithelium in the nose, theolfactory bulb, the piriform cortex, and the prefrontal cortex. Thereceptors detect when an odor is present. The olfactory bulbdiscriminates between odors and whether the odor stems from a pure ormixed odor. The piriform cortex and prefrontal cortices identify (orname) the odorant associated with the pure or mixed odor. Odoradaptation occurs both in the olfactory receptors and in the piriformcortex. Identifying which link in the olfactory system pathway declinespreceding cognitive decline has been difficult. Resolving thisdifficulty is possible with a method of the present invention.Population distributions are generated for at least one odor at eachlink in the olfactory system using the different olfactory measures(detection, discrimination, adaptation and odor identification). Next,an individual is tested with a pure or mixed odor to target each link inthe olfactory system. The test results are then compared to anappropriate population to compute a level metric (Olfaxis Index). Thus,when an assessment is performed, analyzed, and compared to a populationdistribution, the metric results indicate where in the olfactory centralnervous system decline exists. The assessment is also comparedlongitudinally with a subject's own data in one embodiment. This earlyand precise detection, along with medical history and demographicinformation, enables earlier diagnosis and more efficacious therapy toprevent, reverse, or slow the rate of cognitive decline or other healthconditions such as diabetes.

A preferred test using the present system is for testing odor detectionsensitivity, wherein the odor concentration is serially increased ordecreased to identify a person's limit of detection for the specificodorant used. The individual's test data for the specific odorant arecompared against the specific odorant's population distribution withinthe appropriate population database to compute a sensitivity metric(Olfaxis Index). The comparison allows discrimination of smellingability between persons. Further, a concentration threshold for aspecific odorant or mixture of odorants is then generated for theindividual.

Further, testing qualifies a person's smelling ability by stratifyingconcentration thresholds into categories, such as, by way of example andnot limitation, very poor, poor, average, good, and very good. Thecategories may also include the Olfaxis Index of the present invention.Preferably, the sensitivity metric (Olfaxis Index) is determined using aratio of threshold for an olfactory odor (which would change with ageand pathology) to a trigeminal odorant (which may or may not change).The trigeminal odorant is operable to serve as an in person controlagainst which the changed olfactory odorant could be compared.

The database and analyses of the present invention can supportpharmaceutical clinical trials. A pharmaceutical's efficacy is measuredby a person's improvement in smelling ability.

Kiosk

The present invention can also be provided as a kiosk in such places ashealth clubs, medical offices and any other location that could benefitfrom self-testing of olfactory abilities by many persons. The kiosks arepreferably preprogrammed with testing protocols and provide test resultsthat are uploaded anonymously to the population database.

Applications

Numerous applications exist for the systems and methods of the presentinvention. Most prominent is the area of cognitive assessment, aspreviously discussed. Other applications include gaming, market researchand occupational screening and training.

Games

Various possible types of games exist that utilize the presentinvention, including odor puzzles, odor rankings, and odor memory.

Create a Recipe—A game that combines odor puzzles with odor rankings isa game to create a recipe (complex odorant). The game includes thefollowing steps: a player is given at least one odor; the player addscomplementary odors, then shares the “recipe” with a social networkwithout revealing the components. Social networkers smell the blend ofodors, try to guess the components and rate the “recipe”. Data areuploaded into an ad hoc database and each social networker then iscompared to the ad hoc population database.

Mix—In this game the components of a complex odorant are addedsequentially until the player can identify the complex odorant.

Unmix—In this game a masked common odorant is provided. Players attemptto guess the common odorant as they remove masking odors. Masking odorsare removed until they can identify the common odorant.

Market Research

While market research for consumer preferences is known in the art, thesystems and methods of the present invention enable and facilitate thisresearch. Various types of information are obtained, especially thedetection, discrimination, identification and adaptation abilities forindividual odors sorted by demographics, such as ethnicity and age.

“What Does It Need?”—This is a game that combines market research withsocial network gaming. Market researchers provide a base recipe with atleast one missing ingredient to a social network. Players attempt tofind the best ingredient(s) to add. Responses are uploaded to an ad hocdatabase, rated by the social network, and individual rankings reportedback to the players. The results are used by the market researchers toformulate new products.

Odor detection assessment and training

The system of the present invention is used to train an individual'sability to detect specific odors, as shown in FIG. 6. In one embodiment,specific odors include those that are critical to safety. By way ofexample and not limitation, an individual is trained to detect thiols,so that he or she is able to detect a natural gas leak. Other criticalodors include those associated with food spoilage, such as yeast, mold,or bacteria-mediated odors. Thus, the present invention is used toensure that elderly persons are safe to be left alone. Additionally oralternatively, by way of example and not limitation, applications of theodor detection assessment systems and methods of the present inventionare useful for application by insurers to screen applicants for healthcoverage; by employers to verify training, by military to track effectsof training and/or combat, and/or to determine if an elderly or disabledperson is safe left alone (able to detect spoilage, gas, smoke, etc.).

Numerous occupations require that persons be able to detect low levelsof certain odors, or, conversely, not smell low levels of certain odors.For example, many biological processes have highly variable startingingredients and therefore require that the worker be able to sense whena process is complete. In the context of wine, detecting presence of oneodorant in a complex, or one volatile in the wine, is a skill useful oreven required for sommeliers. The ability to smell the completion of aprocess can thus be important. Therefore, the need exists for workers tobe screened and/or trained for their detection level of certain odors,as well as their ability to discriminate and identify the odors when ina complex mixture or masked. An example application is coffee beanroasting. Because of the variability in bean content, the roastingprocess to achieve optimum aroma and reduce undesirable odors due tocharring is variable, and therefore the roaster needs to be able to 1)detect and identify at very low concentrations the odors that signal theonset of charring and 2) adapt to roasting odors in order to detect thecompletion of roasting. The ability to quickly and inexpensively screenand further train these workers satisfies this long-standing, unmet needand results in better coffee.

Method for assessing olfactory system odor detection ability to predictcognitive impairment.

The present invention is also directed to a method for assessingolfactory system odor detection ability to predict the onset of, or beused in conjunction with other medical testing to diagnose cognitiveimpairment, diabetes, traumatic brain injury, ALS, Parkinson's,Alzheimer's, general non-neurodegenerative diseases, general ailments,and the like. The method of the present invention provides for assessingthe odor detection, discrimination and identification ability of ahuman, wherein the results of the assessment are analyzed against anappropriate population database, including demographic databases,medical history databases and the like. Preferably, the results are alsoadded to the appropriate database. The database contains at least onepopulation distribution, wherein a distribution describes a humanpopulation's ability to detect, discriminate between, and/or identifyodors.

The data delivered to a system computing device for analyses and storageis preferably first anonymized. The anonymized data, preferably editedto conform to HIPAA regulations, are aggregated to provide populationdistributions.

FIG. 11 shows a flow diagram illustrating an example method according tothe present invention. This method, which is for determining thedegradation of olfactory performance over time, starts by determiningthe baseline detection level of a person, then determining the detectionlevel over time. The changes in detection level are normalized to ahealthy cohort population change to determine the performance status ofthe tested person.

The above-mentioned examples are provided to serve the purpose ofclarifying the aspects of the invention and it will be apparent to oneskilled in the art that they do not serve to limit the scope of theinvention. By way of example, the system can identify areas needingcritical odor training using analytics and/or rules engines. Further, byway of example and not limitation, the cartridge is provided with atleast one microprocessor having a memory for programming for command andcontrol of the settings of the olfactometer device based upon theparticular odorant(s) within the cartridge, so that the olfactometerdevice automatically provides the correct airflow, etc. for theselective actuation of the predetermined odorant(s) within thecartridge. All modifications and improvements have been deleted hereinfor the sake of conciseness and readability but are properly within thescope of the present invention.

What is claimed is:
 1. A system for assessing, analyzing, andquantifying olfactory system function comprising: at least one olfactorymeasurement apparatus comprising: a compressed gas source, a carriermass gas controller, a stimulus mass gas controller, at least onestimulus odorant cartridge activator with a gas inlet tube and a gasoutlet tube, at least one odorant detector, a mixer, and an output;wherein the compressed gas source produces compressed gas to bechanneled through a stimulus odorant cartridge and the mixer to theoutput; and wherein the carrier mass gas controller and stimulus massgas controller control the carrier gas mass flow and the stimulus gasmass flow, respectively, to provide a predetermined concentration of anodorant in the mixer; wherein the at least one detector measures aconcentration of the odorant; at least one computing device operable tocommunicate over a network with the at least one olfactory measurementapparatus; and a remote database accessible by the computing device overthe network; wherein the at least one computing device receives testresults from the at least one olfactory measurement apparatus and storesthem in the remote database, and wherein the at least one computingdevice compares the test results from the at least one olfactorymeasurement apparatus with test results stored in the remote database;thereby providing a system for providing a test result for assessinggeneral health.
 2. The system of claim 1, further comprising a moduleincluding: an adaptor designed, constructed and configured for acceptingand activating the stimulus odorant cartridge, wherein the stimulusodorant cartridge is a puncture-activated, non-resealable cartridgeincluding an identifier and a headspace, the stimulus odorant cartridgestandardized to provide a predetermined number of tests at apredetermined concentration into a olfactometer; wherein the at leastone detector measures a gas-borne concentration of the odorant in theheadspace of the cartridge; a reader for reading the identifier todetermine information used to regulate gas flow within the cartridge; anair flow generator; and a network port for communicating with thecomputing device to provide testing data to the computing device and theremote database.
 3. The system of claim 1, further comprising at leastone extra headspace cartridge connected to the at least one stimulusodorant cartridge via recirculation tubing.
 4. The system of claim 1,.5. The system of claim 1, wherein the at least one odorant detector ishoused in the gas outlet tube of the activator.
 6. The system of claim1, further including at least one stimulus odorant cartridge with anodorant; wherein the at least one cartridge is a puncture-activated,non-resealable cartridge that is standardized to provide a predeterminednumber of tests at a predetermined concentration and fit into theolfactory measurement apparatus.
 7. The system of claim 6, the systemfurther including at least one cartridge identifier reader and the atleast one stimulus odorant cartridge including an identifier, andwherein the identifier is operable to be read by the reader to determinethe odorant and/or cartridge characteristics.
 8. The system of claim 2,further including at least one stimulus odorant cartridge with anodorant and an identifier; wherein the at least one cartridge is apuncture-activated, non-resealable cartridge that is standardized toprovide a predetermined number of tests at a predetermined concentrationand configured to fit into the at least one olfactory measurementapparatus; and wherein the identifier is operable to be read by the atleast one olfactory measurement apparatus to determine the odorantand/or cartridge characteristics.
 9. The system of claim 2, wherein theat least one olfactory measurement apparatus includes a local database,wherein the local database includes a portion or all of the remotedatabase, wherein the at least one olfactory measurement apparatus isfurther operable to compare the test results from the at least oneolfactory measurement apparatus with test results stored in the localdatabase when a network connection between the at least one computingdevice and the at least one olfactory measurement apparatus is notavailable.
 10. The system of claim 2, further comprising a multiplicityof olfactory measurement apparatuses in real-time communication with theat least one computing device and database.
 11. A method for testingolfactory system function, comprising providing a cartridge-basedolfactometry system; providing a puncture-activated, non-resealablecartridge with an odorant and a headspace, the cartridge standardized toprovide a predetermined number of tests at a predetermined concentrationinto the olfactometer; inserting the cartridge in the olfactometrysystem and activating it; testing an organism.
 12. The method of claim11, wherein the olfactometry system further includes an extra headspacecartridge and the method steps include recirculating the headspace gasbetween the odorant cartridge and the extra headspace cartridge.
 13. Themethod of claim 11, further including the step of the olfactometrysystem detecting the concentration of the odorant in the headspace ofthe odorant cartridge.
 14. The method of claim 11, wherein theolfactometry system further includes a cartridge identifier reader andthe odorant cartridge includes an identifier; the method steps includethe olfactometry system reading the identifier and adjusting the gasflow through the cartridge based on the information from the identifier.15. The method of claim 11, wherein the olfactometry system furtherincludes: a computing device operable to communicate over a network; anda remote database accessible by the computing device over the network;and wherein the computing device receives test results, stores them inthe remote database, and compares them with test results stored in theremote database.
 16. The method of claim 15, wherein the olfactometrysystem includes multiple, geographically distributed testers inreal-time communication with the database and the method steps includethe database updating in real-time with test results from thedistributed testers.
 17. A method for testing olfactory system function,comprising: determining a present minimum concentration of an odorant ina carrier gas needed in an odorant containment structure to obtain apresent positive response to the odorant; creating an Olfaxis Indexbased on the present minimum concentration of the odorant in the carriergas needed in the odorant containment structure to obtain the presentpositive response to the odorant, wherein the Olfaxis Index is createdby: dividing a past minimum concentration of the odorant in the carriergas needed in the odorant containment structure to obtain a pastpositive response by the present minimum concentration of the odorant inthe carrier gas needed in the odorant containment structure to obtainthe positive response to the odorant, or dividing an average pastminimum concentration of the odorant in the carrier gas needed in theodorant containment structure to obtain past positive responses by thepresent minimum concentration of the odorant in the carrier gas neededin the odorant containment structure to obtain the positive response tothe odorant.
 18. The method of claim 17, wherein determining the presentminimum concentration of the odorant in the carrier gas needed in theodorant containment structure to obtain the present positive response tothe odorant includes: providing a predetermined concentration of theodorant in the carrier gas using a carrier gas assembly and an olfactorymeasurement apparatus; delivering the predetermined concentration of theodorant in the carrier gas from the olfactory measurement apparatus tothe odorant containment structure; determining the present positiveresponse to the odorant or a present negative response to the odorant atthe predetermined concentration of the odorant; if the present negativeresponse to the odorant is determined, providing at least one sequentialpredetermined concentration of the odorant in the carrier gas using thecarrier gas assembly and the olfactory measurement apparatus until thepresent positive response is determined, wherein the at least onesequential predetermined concentration of the odorant in the carrier gasis an increased concentration of the odorant in the carrier gas comparedto the predetermined concentration of the odorant in the carrier gas;and upon determining the present positive response, determining thepredetermined concentration of the odorant in the carrier gas or the atleast one sequential predetermined concentration of the odorant in thecarrier gas to be the present minimum concentration of the odorant inthe carrier gas.
 19. The method of claim 17, wherein the presentpositive response to the odorant is given by a user and wherein the pastpositive response is given by the user.
 20. The method of claim 17,wherein the present positive response to the odorant is given by a userand wherein the past positive responses are given by a demographicpopulation having similar age, weight, gender, socioeconomic status,ethnicity, height, genetic predispositions, existing health conditions,and/or combinations thereof to the user.
 21. An apparatus for producinga predetermined concentration of an odorant comprising: a main inlet; amain outlet; a piston assembly including a piston, a piston shaft, and acarrier chamber; a linear potentiometer; a mixing chamber; a scentreservoir; a carrier gas inlet valve controlled by a carrier gas inletsolenoid; a mixture outlet valve controlled by a mixture outletsolenoid; an odor inlet valve controlled by an odor inlet solenoid; anda mixing chamber valve controlled by a mixing chamber solenoid, whereinupon opening of the carrier gas inlet valve, carrier gas flows into theapparatus from a carrier gas assembly; wherein upon opening of the odorinlet valve, the carrier gas flows into the scent reservoir to mix withan odorant in the scent reservoir to create a concentration of odorantin the carrier gas; wherein upon retraction of the piston, the pistonassembly is operable to receive the concentration of odorant in thecarrier gas up to the point of retraction of the piston; wherein uponopening of the mixture outlet valve, opening of the mixing chambervalve, and reverse retraction of the piston, the piston assembly isoperable to force the concentration of odorant in the carrier gasthrough the mixing chamber and out of the main outlet of the apparatus.22. The apparatus of claim 21, further comprising a linear potentiometerfor controlling movement of the piston.
 23. The apparatus of claim 21,further comprising an ultrasonic transducer for activating the odorantin the scent reservoir.
 24. The apparatus of claim 21, furthercomprising a photoionozation detector (PID) for measuring theconcentration of odorant in the carrier gas.
 25. The apparatus of claim21, wherein the carrier gas inlet valve, the mixture outlet valve, theodor inlet valve, and the mixing chamber valve each include an o-ringfor creating an air-tight seal when closed.